In recent years, the accepted treatment for ulcer diseases in the digestive tract has depended upon drugs such as antacids which neutralize gastric acid, anticholinergics and histamine H.sub.2 -receptor antagonists which reduce acid secretion in the stomach, and a drug such as sucralfate which increases the rate of healing of ulcer diseases but does not inhibit gastric acid secretion. The latter compound may have cytoprotective (mucoprotective) effects similar to the prostaglandins and prostaglandin analogs.
However, in stomach and duodenum ulcer diseases induced by stress, which are on increase in recent years, a breakdown of the defensive system of the gastric and duodenal tract can be frequently observed.
As a result of extensive studies of the type of compounds which are useful for prophylaxis and treatment of restraint and water-immersion stress ulcers, it was found that the novel isatin compounds of this invention exhibit anti-ulcer activities which are useful for prophylaxis of stress-induced ulcers caused by restraint and water-immersion in Wister strain rats.
Furthermore, the isatin compounds of this invention have curing effects for acetic acid-induced ulcer diseases, and thus are useful for treatment of chronic ulcer diseases.
The isatin compounds of this invention have prophylactic effects for hydrochloric acid or ethanol-induced gastric mucosal lesions. These findings demonstrate that the isatin compounds of this invention have cytoprotective activities and are useful for prophylaxis and treatment of ulcer diseases.
The isatin compounds of this invention inhibit gastric acid secretion induced by administrating 2-deoxy-D-glucose but do not inhibit gastric acid secretion induced by administrating histamine, carbachol or pentagastrin. These results demonstrate that the novel isatin compounds have gastric acid secretion activities due to certain central nervous system activities. However, the isatin compounds of this invention do not prolong sleeping time or exhibit an inhibition of motor activities.
Isatin 3-semicarbazone derivatives such as isatin 3-semicarbazone, 1-methylisatin 3-semicarbazone, 1-benzylisatin 3-semicarbazone and isatin 3-(4-aminoalkylsemicarbazones) are disclosed in Chem. Rev., Vol. 34, 393 (1944), Chem. Abstr., Vol. 43, 8979g (1949), Chem. Abstr., Vol. 45, 8005g (1951), Chem. Abstr., Vol, 47, 5542f (1953), Chem. Abstr., Vol. 73, 76977b (1970) and Chem. Abstr., Vol. 77, 152122u (1972). However, these reference articles do not indicate any pharmacological effects associated with these disclosed isatin 3-semicarbazone derivatives.
On the other hand, with regard to 1-dialkylaminoalkylisatin 3-thiosemicarbazones, many compounds are disclosed in U.S. Pat. No. 3,374,234, Sci. Pharm., Vol. 38, 98 (1970), J. Med. Chem., Vol. 10, 972 (1967), J. Pharm. Sci., Vol. 68, 459 (1979), Arzneim. Forsch., Vol. 30, 1839 (1980) and Chim. Ther., Vol. 8, 447 (1973). These reference articles disclose that these compounds have pharmacological effects such as antiviral, antibacterial or antifungal effect, and are useful as therapeutic agents.
Specifically, U.S. Pat. No. 3,374,234 above discloses isatin 3-thiosemicarbazones represented by the general formula: ##STR1## wherein Alk represents an alkylene group having 1 to 5 carbon atoms and Z represents an amino group, and indicates that these compounds have pharmacological effects such as antiviral, antibacterial, central stimulating, antihistaminic or analgesic agents, and are useful for therapeutic agents.
With regard to the physical properties of isatin 3-semicarbazones and isatin 3-thiosemicarbazones, Thompson et al. have reported in Chem. Abstr., Vol. 47, 5542f (1953) that antiviral activities of isatin 3-thiosemicarbazones are not found in isatin 3-semicarbazones. Furthermore, Tomchin et al. have reported in Chem. Abstr., Vol. 79, 41782f, 91459b (1973) and Vol. 81, 37145z (1974) thatisatin 3-thiosemicarbazones exist predominantly in the Z-form and isatin 3-semicarbazones are mainly in the E-form and that the isatin 3-semicarbazones in the E-form can be isomerized to the Z-form by heating or treating with an acid. These facts demonstrate that isatin 3-semicarbazones and isatin 3-thiosemicarbazones exhibit different physical properties.